Genetic Contributions to Early Onset Severe Juvenile Arthritis MyD88 is a critical adaptor protein for TLR and IL-1 receptor signaling. Loss-of-function mutations in MyD88 cause severe immunodeficiency, while somatic gain-of-function mutations have been linked to certain lymphomas. We discovered a de novo germline MYD88 mutation in a child with destructive polyarticular juvenile arthritis, and have found that the mutation increases MyD88 oligomerization and NF-kappaB activation. Cells expressing mutant MyD88 overexpress chemokines and cytokines, and some hyper-respond to IL-1beta. Culture supernatants exhibit strikingly enhanced neutrophil chemotactic activity. Thus, this germline MyD88 mutation produces gain-of-function effects in hematopoietic as well as non-hematopoietic cells that are likely to contribute to the development of arthritis. This work has been presented in abstract form at national meetings, and has been published in the Journal of Allergy and Clinical Immunology in May 2018. Future studies will focus on how the mutation or TLR/MyD88 signaling lead to a complex arthritis phenotype. These results support a role for single gene defects contributing to the pathogenesis of JIA.